The retroviruses being studied induce a non-inflammatory neurodegenerative disease in mice which is similar in pathologic features to that caused by the slow unconventional agents such as scrapie. The original viruses which induce this disease were isolated from wild mice in California and causes a paralytic disease associated with tremor after an incubation period of from 3-12 months. A series of chimeric retroviral genomes have been constructed to explore the viral sequences which are necessary for the expression of neurovirulence. In addition to the viral envelope gene which appears to target the viruses to the relevant cells in the central nervous system (CNS) and is a major determinant of the sites of pathology, sequences within the non-translated region of the viral genome have been found to be important in allowing the viruses to replicate to high levels in the CNS. The tempo of the neurodegenerative disease appears to be a function primarily of the nature of a 500 base sequence of the viral genome immediately 5' of the start codon of the structural gene for the gag polyprotein. This observation indicates for the first time that sequences outside the U3 region of the LTR (which contains sequences which regulate transcription) can dramatically influence a retroviral disease. The precise sequence responsible for this effect is currently under investigation. We have found that the CNS is susceptible to infection from day I through day 8 of post-natal life. However, after 8-10 days of age, although the mouse can be productively injected, the CNS becomes highly resistant to infection. This resistance appears to be due to the developmental program of the CNS and does not involve the immune system. We now suspect that this 'window' of susceptibility is an important determinant of the incubation period of the neurologic disease. In the last year we have made a major effort to identify the sites of virus expression in the CNS at both the protein and nucleic acid level. These studies indicate that the spongiform neurodegeneration seen in the motor areas of the CNS is probably due only indirectly to virus replication. Virus replication in one part of the CNS appears to be inducing degeneration in other regions. How this occurs is a matter of intense interest in our laboratory and may bear on the mechanisms of certain neurodegenerative diseases of man.